Topoisomerase I is an enzyme that plays an important and critical role in cellular proliferation. As such, by inhibiting this enzyme, highly proliferative cells are preferentially targeted and unable to propagate. Thus, this enzyme is a highly attractive target for chemotherapeutic agents, especially in human cancers.
Topoisomerase I catalyzes the uncoiling of DNA during replication and transcription. See Pommier et al. (1998), Biochim. Biophys. Acta. 1400(1-3):83-105 and Wang (1996), Annu. Rev. Biochem., 65:635-92. The activity of topoisomerase I is regulated by phosphorylation, primarily on serine residues (Turman et al. (1993) Biochem. Med. Metab. Biol., 50(2):210-25; Coderoni et al. (1990), Int. J. Biochem. 22(7):737-46; Kaiserman et al. (1988), Biochemistry, 27(9):3216-22; Samuels et al. (1992) J. Biol. Chem. 267(16):1156-62)], and appears to be necessary for the initial complex formation between the enzyme and DNA (Coderoni et al. (1990), Int. J. Biochem. 22(7):737-46).
The first topoisomerase I inhibitors to be identified were the camptothecins. Camptothecin (often abbreviated as “CPT”) is a phytotoxic alkaloid first isolated from the wood and bark of Camptotheca acuminata (Nyssaceae). The compound has a pentacyclic ring system with an asymmetric center in lactone ring E with a 20 S configuration. The pentacyclic ring system includes a pyrrolo[3,4-b]quinoline (rings A, B and C), a conjugated pyridone (ring D), and a six-membered lactone (ring E) with a 20-hydroxyl group. Due to its insolubility in water, camptothecin was initially evaluated clinically in the form of a water-soluble carboxylate salt having the lactone ring open to form the sodium salt. In an effort to address the poor aqueous solubility associated with camptothecin and many of its derivatives, a number of synthetic efforts have been directed to derivatizing the A-ring and/or B-ring or esterifying the 20-hydroxyl to improve water-solubility while maintaining cytotoxic activity. For example, topotecan (9-dimethylaminomethyl-10-hydroxy CPT), 10-hydroxy-7-ethyl-camptothecin (also known as SN-38, a metabolite resulting from hydrolysis of irinotecan) and irinotecan (7-ethyl-10[4-(1-piperidino)-1-piperidino]carbonyloxy CPT), otherwise known as CPT-11, are water-soluble CPT derivatives that have shown clinically useful activity. Recently, long acting forms of topoisomerase I inhibitors such as the foregoing have been developed. See, e.g., U.S. Pat. Nos. 8,263,062 and 7,744,861, Zhao, H., et al., Bioconjugate Chem. 2008, 19, 849-859, and Sapra, P., et al., Haematologica, 2009; 94(10), 1456-1459. Such long acting topoisomerase I inhibitors have been shown to be efficacious against a range of human xenograft tumors including breast cancer (Persson, H., et al., AACR-NCI-EORTC Intl Conference on Molecular Targets and Cancer Therapeutics, Oct. 22-26, 2007, S. F. CA. Poster No. C10).
Increasing numbers of patients with diagnosed breast cancer receive primary systemic therapy followed by surgery. In certain cancers such as breast cancer, monitoring a patient's response to treatment is an essential component of therapy, since the degree of response can provide important prognostic information related to disease-free and overall survival. Histopathology provides an accurate assessment of treatment efficacy on the basis of the extent of residual tumor and regressive changes within the tumor tissue. However, only 20% of breast cancer patients achieve a pathologic complete response, a fact that necessitates methods for monitoring therapeutic effectiveness early during therapy (Avril, N. et al., The Journal of Nuclear Medicine, 50 (5) Suppl., May 2009, 55S-63S). Early identification of ineffective therapy may also be useful in patients with metastatic breast cancer due to the number of palliative treatment options. Commonly used methods for assessing efficacy early in treatment include MRI (magnetic resonance imaging), which is expensive and requires both highly specialized equipment and highly trained experts, and radiation-based methods such as CT (computerized axial tomography) scans. New and improved methods for predicting therapeutic effectiveness during treatment of breast cancer, especially those that are efficient, convenient, and cost-effective, could help individualize and customize treatment, and to avoid ineffective chemotherapies.
Thus, there remains a need to provide (among other things) methods for assessing and predicting the efficacy of breast cancer treatment regimens, in particular in patients undergoing therapy with a long-acting topoisomerase-I inhibitor.
The present invention seeks to address these and other needs in the art.